Engagement of the T cell antigen receptor (TCR) results in the activation of protein tyrosine kinases (PTK) and the subsequent tyrosine phosphorylation of numerous proteins (Howe, L. R. and Weiss, A. (1995) Trends Biochem. Sci. 20:59-64; see also Perlmutter, R. M. et al. (1993) Annu. Rev. Immunol. 11:451-499; and Chan, A. C. et al. (1994) Annu. Rev. Immunol. 12:555-592). Efforts to characterize substrates of the TCR induced PTK activity led to the cloning of a 76 kDa protein termed SLP-76 (for SH2-domain-containing Leukocyte Protein of 76 kDa). SLP-76 was originally identified based upon its ability to interact with the protein Grb2, an adaptor molecule involved in coupling signal transduction pathways (Motto, D. et al. (1994) J. Biol. Chem. 269:21608-21613; Reif, K. et al. (1994) J. Biol. Chem. 269:14081-14087; Buday, L. et al. (1994) J. Biol. Chem. 269:9019-9023; and Sieh, M. et al. (1994) Mol. Cell. Biol. 14:4435-4442).
Molecular cloning of SLP-76 cDNAs (human and mouse) revealed that the SLP-76 protein comprises an acidic amino-terminal region, a proline-rich central region and a carboxy-terminal SH2 domain (Jackman J. K. et al. (1995) J. Biol. Chem. 270:7029-7032). Northern analysis demonstrated that SLP-76 mRNA is expressed exclusively in peripheral blood leukocytes, spleen and thymus (Jackman, J. K et al. (1995) supra). Insight into the function of SLP-76 in T cells came from experiments showing that overexpression of SLP-76 augments TCR-mediated signals that lead to the induction of IL-2 gene promoter activity (Motto, D. G. et al. (1996) J. Exp. Med. 183:1937-1943; Wu, J. et al. (1996) Immunity 4:593-602). Interestingly, three distinct regions of SLP-76 that are responsible for protein-protein interactions in T cells are required for the augmentation of IL-2 promoter activity by overexpression of SLP-76 (Fang, N. et al. (1996) J. Immunol. 157:3769-3773; Wardenburg, J. B. et al. (1996) J. Biol. Chem. 271:19641-19644; Musci, M. A. et al. (1997) J. Immunol. 159:1639-1647). These data suggest that SLP-76 functions as a link between proteins that regulate signals generated by TCR ligation.
Certain SLP-76-associated proteins that are thought to participate with SLP-76 in transducing signals from the TCR to the nucleus have been identified. Examples include the protooncogene Vav, which associates with the amino-terminal acidic region of SLP-76 in a phosphotyrosine dependent manner (Wu, J. et al. (1996) Immunity 4:593-602; Onodera, H. et al. (1996) J. Biol. Chem. 271:22225-22230; Tuosto, L. et al. (1996) J. Exp. Med. 184:1161-1167) and SLAP-130, a 130 kDa phosphoprotein that associates with the SH2 domain of SLP-76 and may act as a negative regulator of signal transduction (Musci, M. A. et al. (1997) J. Biol. Chem. 272:11674-11677). However, the precise role of SLP-76 in cells of the hematopoietic lineage is unclear. Accordingly, model systems in which to assess the role of SLP-76 in hematopoietic developments, as well as the involvement of SLP-76 in disease states are needed.